Metastasis is the cause of most cancer-related deaths. The proteolytic degradation of the extracellular matrix is recognized as a mechanism that plays an important role in the metastatic process. Proteolytic enzymes are required to mediate tumor cell invasion into adjacent tissues and initiate the metastatic process. Urokinase plasminogen activator (uPA) is commonly overexpressed by many different human cancers. Conese et al., 1995, Clinical Hematology 8(2):365-389.
The uPA system contains the following elements: (i) Plasminogen—a non-active enzyme that is cleaved to form the active plasmin. Plasmin is a strong proteolytic enzyme able to digest proteins of connective tissue and basement membranes. Plasmin can activate other latent proteolytic enzymes, thus broadening the spectrum of proteins degraded. Pro-collagenase is activated to collagenase in this way. Plasmin is a key enzyme in tissue remodeling, tumor invasion and development of distant metastasis. (ii) Activators—uPA and tissue plasminogen activator (tPA). Both are weak proteolytic enzymes that activate plasminogen to plasmin by proteolytic cleavage. uPA is involved in pericellular proteolysis during cell migration, wound healing, and tissue remodeling under a variety of physiological and pathological conditions. tPA mainly mediates intravascular thrombolysis (Conese et al., 1995, Clin. Hema. 8(2):365-389; Ossowski et al., 1988, J. Cell Biol 107:2437-2445; Jankun et al., 1999, Onco. Rep. 6:523-526). (iii) Inhibitors of plasminogen activators. There are four proteins known for their inhibitory activity toward uPA: PAI-1, PAI-2, PAI-3 and a protein called nexin. (iv) uPAR, a uPA receptor is a glycoprotein that binds uPA to the cell surface. Surface bound uPA retains its ability to activate plasminogen. High numbers of uPA receptors on the surface of cancer cells, if occupied by uPA, create elevated proteolytic activity in the proximity of cancer cells and hence allow dissolution of surrounding tissue which facilitate cancer invasion. Kwaan et al., 1991, Sem. Throm. Hemo. 17:175-182.